THERAPEUTIC EFFICACY OF INHIBITOR OF MITOCHONDRIAL TRANSCRIPTION IN ACUTE MYELOID LEUKEMIA

Abstract

The present research approaches for finding new therapies of acute myeloid leukemia (AML) are much focused on targeting the different genetic alterations in AML but many of them fail, probably due to the heterogeneity of the leukemic cells to be targeted. Recently, mitochondrial dependency is shown to play an important role in the progression of AML. AML cells exhibit high expression of mitochondrial RNA polymerase (POLRMT) which indirectly leads to high oxidative phosphorylation. Based on its upregulation as well as unique structure, POLRMT would have a great potential as a therapeutic target in AML. Recently, a novel inhibitor of mitochondrial transcription (IMT) has been developed which exhibits an anti-cancer potential by specifically targeting POLRMT. Here, we investigated the effect of IMT on AML. First, we showed that AML cell lines are sensitive to IMT. We could see a significant decline in proliferation in all human AML cell lines in a concentration-dependent manner, acquired by measurement of ATP production. Next, we investigated the effect of IMT in vivo in immunodeficient mice which were transplanted with an AML cell line that harbors FLT3-ITD mutation. IMT was administrated for 21 days from two weeks post-transplantation and compared with mice either treated with AC220 (FLT inhibitor) or vehicle (n=10/group). Results show that IMT was well tolerated by the mice and there was no sign of toxicity in normal tissues despite a significant delay or prevention of the onset of leukemia. Median survival of IMT treated mice=114 days vs vehicle treated=45 days (p